1. Field of the Invention
The present invention relates to a crystal of a synthetic intermediate of a 2-substituted-1β-methyl carbapenem compound useful as antimicrobial agents.
2. Background Art
2-Substituted-1β-methyl carbapenem compounds are known to be useful as antimicrobial agents. In the derivation of various 2-substituted-1β-methyl carbapenem compounds, compounds of formula (I) are important intermediates therefor.
wherein TBS represents t-butyldimethylsilyl; and Ph represents phenyl.
For example, J. Med. Chem., 30, 871 (1987) describes the synthesis of 2-aryl-1β-methyl carbapenem from the compound of formula (I) (see scheme 1 below). This document reports that the resultant compound has higher antimicrobial activity against Staphylococcus aureus, Enterococcus, Escherichia coli and the like than imipenem (IPM) and has higher stability against renal DHP-1 than IPM.
wherein TBS and Ph are as defined above; PySSPy represents 2,2′-dipyridyldisulfide; Ar represents aryl; TBAF represents tetrabutylammonium fluoride; and Ac represents acetyl. The triangular symbol means that heating (for example, 80 to 150° C.) is carried out.
J. Antibiotics, 41, 780 (1988) describes the synthesis of 2-ureido-1β-methyl carbapenem from the compound of formula (I) (see scheme 2 below). This document reports that the resultant compound has higher antimicrobial activity against Enterococcus, Escherichia coli, Klebsiella pneumoniae and the like than IPM and has higher stability against renal DHP-1 than IPM.
wherein TBS, Ph, and PySSPy are as defined above; DMAP represents 4-N,N-dimethylaminopyridine; LDA represents lithium diisopropylamide; R represents a hydrogen atom, optionally substituted alkyl, phenyl or the like; Me represents methyl; and Alloc represents allyloxycarbonyl. The triangular symbol means that heating (for example, 80 to 150° C.) is carried out.
WO 96/28455 by the present inventors describes the synthesis of 2-imidazo[5,1-b]thiazoliummethyl-1β-methyl carbapenem from the compound of formula (I) (see scheme 3 below). This document reports that the resultant compound has higher antimicrobial activity against Staphylococcus aureus including MRSA, Enterococcus, Escherichia coli, pneumococci, Pseudomonas aeruginosa and the like than IPM and has higher stability against renal DHP-1 than IPM.
wherein TBS, Ph, PySSPy, DMAP, LDA, Me, and Alloc are as defined above. The triangular symbol means that heating (for example, 80 to 150° C.) is carried out.
WO 01/53305 describes the synthesis of 2-(7-methylthioimidazo[5,1-b]thiazolyl)-1β-methyl carbapenem from the compound of formula (I) (see scheme 4 below). This document reports that the resultant compound has higher antimicrobial activity against Staphylococcus aureus, Enterococcus, pneumococci including PRSP, Haemophilus influenzae including ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis and the like than IPM and has higher stability against renal DHP-1 than IPM.
wherein TBS, Ph, and Me are as defined above; Et represents ethyl; and X represents a halogen atom. The triangular symbol means that heating (for example, 80 to 150° C.) is carried out.
The structures and synthetic processes for compounds of formula (I) are known to a person having ordinary skill in the art. However, as described, for example, in J. Med. Chem., 30, 871 (1987) (particularly page 876, right column), regarding compounds of formula (I) (corresponding to compound 16 in the above document), any crystal form was not produced although “light brown thick oils” were obtained.
In the production of contemplated carbapenem antimicrobial compounds on a commercial scale, the compound of formula (I) in the thick oil form was not easy to handle. Further, when the oil compound is purified for improving the yield of the final target compound, for example, treatment with a column using a large amount of silica gel is necessary, leading to increased cost.
Thus, compounds of formula (I) not in a crystal form have hitherto been known. So far as the present inventors know, however, crystal forms of compounds of formula (I) have not been known up to now, and even an attempt to produce such crystal form has not been made.